Chitosan oral patches inspired by mussel adhesion.

Oral mucosal drug delivery systems have been developed to expedite the regeneration of oral mucosa, there are still many challenges related to residence time for drugs because the ceaseless changes of saliva, mouth movement, and involuntary swallowing prevent robust adhesion of drugs and/or drug-loaded biomaterials. Thus, it is highly desirable to develop the delivery platforms exhibiting robust, stable adhesion within oral cavities. Herein, we have developed an adhesive polysaccharide oral patch called 'Chitoral' that utilizes chemical principles shown in wet-resistant mussel adhesion. Chitoral plays an important role as an adhesive layer in wet environments. We unexpectedly found that Chitoral instantly dissolves upon contact with saliva and a labial mucous layer, and then the dissolved Chitoral compounds forms an insoluble adhesion layer with mucins at Chitoral/mucous interface nearly immediate actions. Later, Chitoral gradually converts into adhesive hydrogels by the cooperative actions of covalent crosslinking and physical entanglement. The instant, robust muco-adhesion properties of Chitoral provides long-lasting therapeutic effects of drugs resulting enhanced healing of oral ulcer. Thus, mussel-inspired, mucous-resistant adhesive platforms, Chitoral, can be a platform for oral mucosal drug delivery systems.

Hemostatic Swabs Containing Polydopamine-like Catecholamine Chitosan-Catechol for Normal and Coagulopathic Animal Models.

All animal experiments for evaluating drug efficacy or developing medical devices are unavoidably accompanied by bleeding that result in unreliable outcomes with large variations between individuals. Herein, we developed hemostatic swabs prepared by a mussel-inspired catecholamine polymer called chitosan-catechol, which was inspired by the chemical composition of the well-known material-independent coating material of polydopamine. The hemostatic ability of the swabs resulted from the formation of self-sealing membranes by rapid intermolecular interactions between whole blood proteins and the applied chitosan-catechol. The blood protein/chitosan-catechol composite sealing membrane resulted in dramatic decreases in bleeding for both normal and coagulopathic models, such as diabetes.

Complete prevention of blood loss with self-sealing haemostatic needles.

Bleeding is largely unavoidable following syringe needle puncture of biological tissues and, while inconvenient, this typically causes little or no harm in healthy individuals. However, there are certain circumstances where syringe injections can have more significant side effects, such as uncontrolled bleeding in those with haemophilia, coagulopathy, or the transmission of infectious diseases through contaminated blood. Herein, we present a haemostatic hypodermic needle able to prevent bleeding following tissue puncture. The surface of the needle is coated with partially crosslinked catechol-functionalized chitosan that undergoes a solid-to-gel phase transition in situ to seal punctured tissues. Testing the capabilities of these haemostatic needles, we report complete prevention of blood loss following intravenous and intramuscular injections in animal models, and 100% survival in haemophiliac mice following syringe puncture of the jugular vein. Such self-sealing haemostatic needles and adhesive coatings may therefore help to prevent complications associated with bleeding in more clinical settings.

Adhesive barrier/directional controlled release for cartilage repair by endogenous progenitor cell recruitment.

A new design concept in controlled release chemistry is reported in this study. Unlike current depots that release drugs in all direction by an isotropic way, we demonstrate that directional release only to a clinically beneficial direction results in improved disease treatment. To achieve the directional drug release, catecholamine adhesion chemistry was used to establish robust interfacial adhesion. For this purpose, water-resistant catechol-conjugated chitosan (CHI-C) adhesive gel patch was used. We chose a cartilage repair model to test our hypothesis. The adhesive barrier exhibited directional release of platelet-derived growth factor-AA (PDGF-AA) only toward the marrow cavity defect areas. This directional PDGF-AA release greatly promoted effective recruitment of human mesenchymal stem cell (hMSCs). Moreover, the adhesive barrier prevented further migration and dispersion of the hMSCs that otherwise were not properly located to the disease site. In vivo imaging and macroscopic histological assessments demonstrated significant improvement of cartilage tissue, suggesting directional controlled release can be a general concept for improvement of tissue regeneration. This CHI-C barrier is expected to make a significant contribution in cartilage tissue engineering without cell transplantation as well as application for other tissue engineering.

Effects of recombinant human bone morphogenic protein-2 and human bone marrow-derived stromal cells on in vivo bone regeneration of chitosan-poly(ethylene oxide) hydrogel.

In vivo bone regeneration of chitosan-poly(ethylene oxide) (PEO) hydrogel in rat carlvarial defects was evaluated by using both human bone marrow-derived stromal cells (hMSCs) and recombinant human bone marrow protein-2 (rhBMP-2) for 4 and 8 weeks. In situ chitosan-PEO hydrogel was fabricated by mixing the precursor solutions of both chitosan-acrylate and PEO-thiol. Fabrication of the injectable hydrogels was modulated from within a minute to hours by controlling the temperature and pHs of the precursor solution. Gel swellings were dependent on the conditions of pHs and temperatures of the precursor solutions, showing higher gel swelling in basic water than in either acidic or neutral water. The compression strengths and in vitro degradation of hydrogels were also evaluated by controlling the concentrations of both precursor solutions and lysozyme, respectively, by referencing to the morphology of the control hydrogel with no enzyme added. Hydrogels showed sustained release of rhodamine-B over time. After implantation of the injectable hydrogels in rat calvarial defects for 4 and 8 weeks, in vivo bone regenerations were compared with by evaluating the degrees of new bone formations with Soft X-ray, microcomputed tomography, and histological stainings of hematoxylin and eosine Y and Masson's trichrome. Degrees of in vivo bone regeneration were controlled by encapsulating in advance either hMSCs, rhBMP-2, or both in the precursor solutions of the hydrogel. The defect implanted with hydrogel only showed higher amount of bone tissue regeneration than that of the control defect site. The defect sites with hydrogel containing both hMSCs and rhBMP-2 demonstrated highest amount of bone tissue regeneration among the samples.